HCV 2014 and beyond the interferon era Patrick M. Horne, MSN, ARNP, FNP-BC Assistant Director of Hepatology Clinical Research Division of Gastroenterology, Hepatology and Nutrition University of Florida Health Disclosures and Off-label Discussion • Financial relationships to disclose within the past 12 months: • Scientific consultant for Gilead Sciences • Off-label discussion: • Combination sofosbuvir + simeprevir Objectives • Discuss the history and worldwide prevalence of hepatitis C • Review the current approved therapeutic options for HCV therapy based on genotype • Discuss some future treatment options in development Direct Acting Antivirals Nucleoside inhibitor Protease 2013 inhibitor Developments in Treatment and Cure Rates Peginterferon 2011 2001 >70% Ribavirin 55% 1998 SVR (%) SVR % Standard Interferon 42% 34% 1991 16% 6% TIME >90% Seroprevalence of Hepatitis C: 170 to 200 Million Worldwide Eastern Europe 10 M United States 5M Americas 12-15 M Western Pacific 60 M Western Europe 5M Highest Prevalence: Egypt-4M (45% adults >40y) Africa 30-40M Southeast Asia 30-35 M Australia .2 M 1. World Health Organization. Wkly Epidemiol Rec. 2000;75:17-28. 2. Edlin B et al. AASLD; November 11-15; 2005 San Francisco, California. Oral Presentation #44. P-DS-D-159 SVR is Associated with Reduced Mortality Among HCV-infected Persons 30 P<0.001 Liver-related mortality or liver transplantation, % All-cause mortality, % • 530 adults in Europe prospectively followed for median 8.4 years after HCV treatment All-cause mortality Liver-related mortality or liver 30 • 192 (36%) achieved SVR transplantation 20 10 Without SVR 0 0 1 2 3 4 5 With SVR 6 7 8 9 P<0.001 20 Without SVR 10 0 10 0 Time, y No. at risk Without SVR With SVR 405 393 382 363 344 317 295 250207 164 135 192 181 168 162 156 144 125 88 56 40 28 Van der Meer, et al. JAMA 2012:308:2584-2593. With SVR 1 2 3 4 5 6 7 8 9 10 Time, y No. at risk Without SVR With SVR 405 392 380 358 334 305 277 229 187 146 119 192 181 168 162 156 144 125 88 56 40 28 75% of Infected Individuals Are Not Aware of Their HCV Status 1. Institute of Medicine. Hepatitis and Liver Cancer, A National Strategy for Prevention and Control of Hepatitis B and C. Washington, DC. The National Academies Press, 2010; 2.United States Department of Health and Human Services. Combating the Silent Epidemic of Viral Hepatitis, Action Plan for the Prevention, Care & Treatment of Viral Hepatitis. 2011 CDC Releases Birth Cohort Screening Guidelines • Adults born during 1945–1965 should receive one-time testing for HCV without prior ascertainment of HCV risk • All persons identified with HCV infection should receive a brief alcohol screening and intervention as clinically indicated, followed by referral to appropriate care and treatment services Smith BD, et al. MMWR Recomm Rep. 2012;61(RR-4):1-32. Case 1 • 60 year old Caucasian male presents recently found to be HCV Ab positive. – Confirmatory testing confirms genotype 1a with a viral load of 1,245,300 IU/mL. • Hx of illicit drug use in the 1960s • Medical hx includes – Hypertension-well controlled – GERD-well controlled with PPI Case 1 • Naïve to treatment • Baseline labs: – AST 66, ALT 70 – Total bilirubin 0.5 – Hemoglobin 14.0 – Platelet count 175,000 – Fibrotest=F2 disease Case 1 • What do you do? Current options • Approved options – Pegylated interferon (Peg-INF) and ribavirin (RBV), weight based times 48 weeks – Peg-INF, RBV plus either telaprevir (TVR) or bocepravir (BOC) for 24-48 weeks – Peg-INF, RBV plus simeprevir (SIM) for 24-48 weeks – Peg-INF, RBV plus sofosbuvir (SOF) times 12 weeks or SOF and RBV for 24 weeks Current options • Not approved option but with good data – SOF + SIM with or without ribavirin for 12 weeks- COSMOS study • Wait for something else 100 90% 90 75% 80 80% 76% 70 60 50% 50 40 30 20 10 0 Peg-INF/RBV Package inserts PEG-INF/RBV/TVR or BOC Peg-INF/RBV/SIM Peg-INF/RBV/SOF SOF/RBV Recommendations for HCV Genotype 1 Treatment-Naïve Population Recommended Regimen Duration Treatment-naïve genotype 1 Sofosbuvir (400 mg) + PEG-INF + RBV (1000-1200 mg/d) 12 weeks • Alternative regimens: • Simeprevir + PEG-INF+ RBV x 12 wks • SIM + SOF+/- RBV x 12 wks • SOF + RBV x24 wks • Regimens specifically not recommended: • Peg-INF/RBV x 48 wks with or without TVR or BOC • Monotherapy with PEG, RBV, or DAA Peg-INF = pegylated interferon; RBV=ribavirin; DAA = direct acting antiviral AASLD/IDSA Treatment Recommendations. www.hcvguidelines.org. Accessed January 31, 2014. Neutrino Study Overall 1 (1a, 1b, 1a/b) HCV GT 1a 1b 4, 5, 6 SOF + PEG-IFN + RBV Cirrhosis SVR by Subgroups Race HCV RNA level IL28B No Yes Black Non-black <6 log10 IU/mL ≥6 log10 IU/mL CC Non-CC SVR Lawitz E, et al. EASL 2013, Abstract 1411; Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. SVR % 60 70 80 90 100 Genotype 1 Treatment Options Phase 3 Landscape SVR (est) 2014 (now) 90% PEG/RBV + SOF > 90% SOF + SMV (off-label) 60-70% SOF + RBV (select populations) 12 1212 weeks 0 00 24-48 2014-2015 SOF + LPV + RBV > 94% ABT-450+ 333 + 267 + RBV >94% DCV + ASU (1b) 90% SOF + DCV > 94% Courtesy of David Nelson, M.D. Case 2 • 55 year old African-American female with HCV genotype 2b who was a prior relapser to Peg-INF + RBV times 24 weeks. • Liver biopsy in 2013-F3 fibrosis • Other medical hx: – Diabetes – Hyperlipidemia – Anxiety Case 2 • Labs: – HCV RNA 550,000 IU/mL – AST 100, ALT 98 – Total bilirubin 1.0 – Hemoglobin 12.5 – Platelet count 110,000 Case 2 • What do you do? Options • Re-treat with Peg-INF + RBV for 48 weeks – Prior treatment she required multiple dose reductions of Peg-INF due to side effects • SOF + RBV for 12 weeks • Wait Recommendations for HCV Genotype 2 Treatment-Experienced Population Recommended Regimen Duration Previous treatment with PEG/RBV Sofosbuvir (400 mg) + RBV (1000-1200 mg/d) 12 weeks* *Patients with cirrhosis may benefit by extension of therapy to 16 weeks Population Alternative Regimen Previous treatment with Sofosbuvir (400 mg) + PEG-IFN + PEG/RBV RBV (1000-1200 mg/d) Duration 12 weeks AASLD/IDSA Treatment Recommendations. www.hcvguidelines.org. Accessed January 31, 2014. Sofosbuvir + RBV in HCV GT 2/3 Genotype 2 = 3 FISSION GT-2 GT-3 12 week GT-2 97% 12 Week 5656%% 93% 12 week POSITRON 12 week 61% 12 week FUSION FUSION 12 week 86% 30% GT-3 94% 16 week FUSION 16 week 62% 12 week VALENCE 93% 62% 24 week SVR12 rate (%) 0 10 Lawitz E, et al. N Engl J Med 2013;368:1878-87. 20 30 40 50 84% 60 70 80 90 100 Jacobson IM, et al. N Engl J Med 2013;368:1867-77. 23 Case 3 • 54 year old Hispanic male with HCV genotype 3. – Diagnosed 5 years ago – Relapser to Peg-INF and RBV – Liver biopsy 2013-F1 fibrosis • Other medical history: – Bipolar disorder – GERD – Arthritis Case 3 • Labs: – HCV RNA 1,200,000 IU/mL – AST 55, ALT 80 – Total bilirubin 0.6 – Hemoglobin 13.4 – Platelet count 200,000 Treatment options • Peg-INF + RBV for 24 weeks • SOF + RBV for 24 weeks • Peg-INF + RBV + SOF for 12 weeks Recommendations for HCV Genotype 3, Treatment – Naïve/Experienced Population Recommended Regimen Duration Regardless of IFN eligibility Sofosbuvir (400 mg) + RBV (1000-1200 mg/d) 24 weeks Population Alternative Regimen Duration Consider only if eligible for IFN Sofosbuvir (400 mg) + Peginterferon + RBV (1000-1200 mg/d) 12 weeks Not recommended: • PEG/RBV • Telaprevir, boceprevir, simeprevir AASLD/IDSA Treatment Recommendations. www.hcvguidelines.org. Accessed January 31, 2014. Sofosbuvir + RBV in HCV GT 2/3 Genotype 2 = 3 FISSION GT-2 GT-3 12 week GT-2 97% 12 Week 5656%% 93% 12 week POSITRON 12 week 61% 12 week FUSION FUSION 12 week 86% 30% GT-3 94% 16 week FUSION 16 week 62% 12 week VALENCE 93% 62% 24 week SVR12 rate (%) 0 10 Lawitz E, et al. N Engl J Med 2013;368:1878-87. 20 30 40 50 84% 60 70 80 90 100 Jacobson IM, et al. N Engl J Med 2013;368:1867-77. 28 VALENCE: Sofosbuvir + RBV Genotype 3 IFN naïve, ineligible or treatment failures 0 weeks 12 24 G3 SOF+RBV (n=250) 100 80 93 92 85 60 SVR 12 (%) 60 40 20 86/92 12/13 85/100 27/45 0 Noncirrhotic Naïve Zeuzem S et al, AASLD 2013, #1085 Cirrhotic Noncirrhotic Cirrhotic Treatment-experienced Impact of Duration on Efficacy of SOF in Tx-experienced GT 3 FUSION: 12 Weeks SOF/RBV FUSION: 16 Weeks SOF/RBV VALENCE: 24 Weeks SOF/RBV 100 85 80 63 SVR12 (%) 60 40 60 14/ 23 27/ 45 37 19 20 n/N = 0 61 14/ 38 25/ 40 85/ 100 5/ 26 No Cirrhosis Cirrhosis Genotype 3 SOF = sofosbuvir; RBV=ribavirin Lawitz E, et al. AASLD 2013. Zeuzem, et al. AASLD 2013. Lonestar-2 Peg-INF + RBV + SOF times 12 weeks Lawitz E AASLD 2013 What about waiting? • What may be coming? Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 2-3 Treatment-Naïve 24 Week Rx Week Rx Naïve GT 2 or 3 n = 44 0 12 24 36 n = 16 SOF × 7 days, then DCV + SOF SVR12 = 88% n = 14 DCV + SOF SVR12 = 93% n = 14 DCV + SOF + RBV SVR12 = 86% Drug Dosing Daclatasvir (DCV): 60 mg once daily Sofosbuvir (SOF): 400 mg once daily Genotype 3 (n= 150) - naïve - experienced • Phase 3 Trial (NCT02032901): ongoing, but closed to enrollment DCV + SOF Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.; Clinical Trials.gov Core E1 Protease HCV PIs Viral enzyme Active site Telaprevir Boceprevir Simeprevir Faldaprevir Asunaprevir ABT-450 MK-5172 Sovaprevir ACH-2684 E2 NS2 NS3 NS5A Inhibitors Non-enzyme Replication complex Daclatasvir Ledipasvir ABT-267 GS-5816 ACH-3102 PPI-668 GSK2336805 Samatasvir MK-8742 Courtsey of David Nelson, M.D. 4A 5’UTR p7 The New Era of HCV Therapy Multiple Direct Acting Antivirals NS4B NS5A 3’UTR NS5B Polymerase NS5B Nucs NS5B Non-nucs Viral enzyme Active site Viral enzyme Allosteric site Sofosbuvir VX-135 IDX20963 ACH-3422 ABT-333 Deleobuvir BMS-791325 PPI-383 GS-9669 TMC647055 HCV Future Treatment Paradigm Many Options to Choose From Direct Acting Antivirals IL28B CC SOF + RBV SOF + PI SOF + NS5A NS5A + PI PEG-IFN + RBV + RBV + RBV + NNI + RBV + DAA NI: nucleotide polymerase inhibitor (SOF), NNI: non-nucleotide polymerase inhibitor PI: protease inhibitor, NS5A: NS5A replication complex inhibitor Summary • Large cohort of patients that have yet to be diagnosed. • Treatment options are becoming better and short and more individualized. • More patients will have access to medications options as we will no longer be limited by contraindications to treatment due to medical co-morbidities or side effects Thank you!